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108. Automated radiosynthesis of the adenosine A2A receptor‐targeting radiotracer [18F]FLUDA.

Author

Lai, Thu Hang, Wenzel, Barbara, Moldovan, Rareş‐Petru, Brust, Peter, Kopka, Klaus, and Teodoro, Rodrigo

Subjects
RADIOACTIVE tracers, ADENOSINES, POSITRON emission tomography, RADIOCHEMICAL purification
Abstract

[18F]FLUDA is a selective radiotracer for in vivo imaging of the adenosine A2A receptor (A2AR) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [18F]FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [18F]FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one‐pot two‐step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69–333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [18F]FLUDA. [ABSTRACT FROM AUTHOR]

Published
2022
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110. Quantitation of the A 2A Adenosine Receptor Density in the Striatum of Mice and Pigs with [ 18 F]FLUDA by Positron Emission Tomography.

Author

Gündel, Daniel, Toussaint, Magali, Lai, Thu Hang, Deuther-Conrad, Winnie, Cumming, Paul, Schröder, Susann, Teodoro, Rodrigo, Moldovan, Rareş-Petru, Pan-Montojo, Francisco, Sattler, Bernhard, Kopka, Klaus, Sabri, Osama, and Brust, Peter

Subjects
POSITRON emission tomography, ADENOSINES, MICE, SWINE, PARKINSON'S disease, HUNTINGTON disease, NEURODEGENERATION
Abstract

The cerebral expression of the A2A adenosine receptor (A2AAR) is altered in neurodegenerative diseases such as Parkinson's (PD) and Huntington's (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A2AAR–specific antagonist radiotracer [18F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (BPND) of [18F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (VT) at baseline and under blocking conditions with tozadenant. The MRT of [18F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A2AAR antagonist istradefylline. Mouse results showed the highest BPND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A2AAR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the VT (14.6 vs. 8.5 mL · g−1) and BPND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BPND of [18F]FLUDA in the striatum. We conclude that [18F]FLUDA is a suitable tool for the non–invasive quantitation of altered A2AAR expression in neurodegenerative diseases such as PD and HD, by PET. [ABSTRACT FROM AUTHOR]

Published
2022
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112. Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease

Author

Schaffernicht, Gabriela, primary, Shang, Qi, additional, Stievenard, Alicia, additional, Bötzel, Kai, additional, Dening, Yanina, additional, Kempe, Romy, additional, Toussaint, Magali, additional, Gündel, Daniel, additional, Kranz, Mathias, additional, Reichmann, Heinz, additional, Vanbesien-Mailliot, Christel, additional, Brust, Peter, additional, Dieterich, Marianne, additional, Funk, Richard H. W., additional, Ravens, Ursula, additional, and Pan-Montojo, Francisco, additional

Published
2021
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114. Development of 18F-Labeled Radiotracers for PET Imaging of the Adenosine A2A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation

Author

Lai, Thu Hang, primary, Schröder, Susann, additional, Toussaint, Magali, additional, Dukić-Stefanović, Sladjana, additional, Kranz, Mathias, additional, Ludwig, Friedrich-Alexander, additional, Fischer, Steffen, additional, Steinbach, Jörg, additional, Deuther-Conrad, Winnie, additional, Brust, Peter, additional, and Moldovan, Rareş-Petru, additional

Published
2021
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115. Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

Author

Gündel, Daniel, primary, Sadeghzadeh, Masoud, additional, Deuther-Conrad, Winnie, additional, Wenzel, Barbara, additional, Cumming, Paul, additional, Toussaint, Magali, additional, Ludwig, Friedrich-Alexander, additional, Moldovan, Rareş-Petru, additional, Kranz, Mathias, additional, Teodoro, Rodrigo, additional, Sattler, Bernhard, additional, Sabri, Osama, additional, and Brust, Peter, additional

Published
2021
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116. Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Author

Jevtić, Ivana I., Lai, Thu Hang, Penjišević, Jelena, Dukić-Stefanović, Slađana, Andrić, Deana, Brust, Peter, Kostić-Rajačić, Slađana, and Teodoro, Rodrigo

Subjects
lcsh:QD241-441, Molecular Docking Simulation, Inhibitory Concentration 50, positron emission tomography, lcsh:Organic chemistry, Halogenation, Protein Conformation, Communication, piperazine, Monoamine Oxidase, MAO-B, cinnamic acid, Protein Binding
Abstract

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.

Published
2020

117. Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using (S)-(−)-[18F]Fluspidine in Glioblastoma

Author

Toussaint, Magali, Deuther-Conrad, Winnie, Kranz, Mathias, Fischer, Steffen, Ludwig, Friedrich-Alexander, Juratli, Tareq A., Patt, Marianne, Wünsch, Bernhard, Schackert, Gabriele, Sabri, Osama, and Brust, Peter

Subjects
lcsh:QD241-441, orthotopic xenograft of glioblastoma in mouse, sigma-1 receptor availability, lcsh:Organic chemistry, (S)-(−)-[18F]fluspidine, ddc:540, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710, small animal Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI), imaging-based biomarker, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710
Abstract

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (S)-(&minus, )-[18F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical KD values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.

Published
2020
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119. Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Author

Jevtić, Ivana, Lai, Thu Hang, Penjišević, Jelena, Dukić-Stefanović, Sladjana, Andrić, Deana, Brust, Peter, Kostić Rajačić, Slađana, Teodoro, Rodrigo, Jevtić, Ivana, Lai, Thu Hang, Penjišević, Jelena, Dukić-Stefanović, Sladjana, Andrić, Deana, Brust, Peter, Kostić Rajačić, Slađana, and Teodoro, Rodrigo

Abstract

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.

Published
2020

120. Preclinical Incorporation Dosimetry of [18F]FACH—A Novel 18F-Labeled MCT1/MCT4 Lactate Transporter Inhibitor for Imaging Cancer Metabolism with PET

Author

Sattler, Bernhard, Kranz, Mathias, Wenzel, Barbara, Jain, Nalin T., Moldovan, Rare¸s-Petru, Toussaint, Magali, Deuther-Conrad, Winnie, Ludwig, Friedrich-Alexander, Teodoro, Rodrigo, Sattler, Tatjana, Sadeghzadeh, Masoud, Sabri, Osama, Brust, Peter, Sattler, Bernhard, Kranz, Mathias, Wenzel, Barbara, Jain, Nalin T., Moldovan, Rare¸s-Petru, Toussaint, Magali, Deuther-Conrad, Winnie, Ludwig, Friedrich-Alexander, Teodoro, Rodrigo, Sattler, Tatjana, Sadeghzadeh, Masoud, Sabri, Osama, and Brust, Peter

Abstract

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron emission tomography (PET). Here, the organ doses (ODs) and the effective dose (ED) of the first 18F-labeled MCT1/MCT4 inhibitor were estimated in juvenile pigs. Whole-body dosimetry was performed in three piglets (age: ~6 weeks, weight: ~13–15 kg). The animals were anesthetized and subjected to sequential hybrid Positron Emission Tomography and Computed Tomography (PET/CT) up to 5 h after an intravenous (iv) injection of 156 ± 54 MBq [18F]FACH. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time–activity data. Time and mass scales were adapted to the human order of magnitude and the ODs calculated using the ICRP 89 adult male phantom with OLINDA 2.1. The ED was calculated using tissue weighting factors as published in Publication 103 of the International Commission of Radiation Protection (ICRP103). The highest organ dose was received by the urinary bladder (62.6 ± 28.9 µSv/MBq), followed by the gall bladder (50.4 ± 37.5 µSv/MBq) and the pancreas (30.5 ± 27.3 µSv/MBq). The highest contribution to the ED was by the urinary bladder (2.5 ± 1.1 µSv/MBq), followed by the red marrow (1.7 ± 0.3 µSv/MBq) and the stomach (1.3 ± 0.4 µSv/MBq). According to this preclinical analysis, the ED to humans is 12.4 µSv/MBq when applying the ICRP103 tissue weighting factors. Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%, the conversion factor applied for estimation of the ED to humans would rise to 20.6 µSv/MBq. In this case, the ED to humans upon an iv application of ~300 MBq [18F]FACH would be about 6.2 mSv. This risk assessment encourages the translation of [18F]FACH into clinic

Published
2020

123. Physiological and pathological changes in the enteric nervous system of rotenone-exposed mice as early biomarkers for Parkinson’s disease

Author

Schaffernicht, Gabriela, primary, Shang, Qi, additional, Stievenard, Alicia, additional, Bötzel, Kai, additional, Dening, Yanina, additional, Kempe, Romy, additional, Toussaint, Magali, additional, Gündel, Daniel, additional, Kranz, Mathias, additional, Reichmann, Heinz, additional, Vanbesien-Mailliot, Christel, additional, Brust, Peter, additional, Dieterich, Marianne, additional, Funk, Richard H.W., additional, Ravens, Ursula, additional, and Pan-Montojo, Francisco, additional

Published
2020
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126. Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [ 18 F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain.

Author

Clauß, Oliver, Schäker-Hübner, Linda, Wenzel, Barbara, Toussaint, Magali, Deuther-Conrad, Winnie, Gündel, Daniel, Teodoro, Rodrigo, Dukić-Stefanović, Sladjana, Ludwig, Friedrich-Alexander, Kopka, Klaus, Brust, Peter, Hansen, Finn K., and Scheunemann, Matthias

Subjects
RADIOACTIVE tracers, DEACETYLASES, POSITRON emission tomography, NUCLEOPHILIC substitution reactions, BRAIN tumors, RADIOCHEMICAL purification
Abstract

The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work is the development of a novel 18F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). BA3, exhibiting high inhibitory potency for HDAC1 (IC50 = 4.8 nM) and HDAC2 (IC50 = 39.9 nM), and specificity towards HDAC3 and HDAC6 (specificity ratios >230 and >2080, respectively), was selected for radiofluorination. The two-step one-pot radiosynthesis of [18F]BA3 was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [18F]BA3 resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (n = 5, EOS). For the characterization of BA3, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of BA3, whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound. [ABSTRACT FROM AUTHOR]

Published
2022
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129. Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Author

Grachev, Igor D., primary, Meyer, Philipp M., additional, Becker, Georg A., additional, Bronzel, Marcus, additional, Marsteller, Doug, additional, Pastino, Gina, additional, Voges, Ole, additional, Rabinovich, Laura, additional, Knebel, Helena, additional, Zientek, Franziska, additional, Rullmann, Michael, additional, Sattler, Bernhard, additional, Patt, Marianne, additional, Gerhards, Thilo, additional, Strauss, Maria, additional, Kluge, Andreas, additional, Brust, Peter, additional, Savola, Juha-Matti, additional, Gordon, Mark F., additional, Geva, Michal, additional, Hesse, Swen, additional, Barthel, Henryk, additional, Hayden, Michael R., additional, and Sabri, Osama, additional

Published
2020
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130. (+)-[18F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand—results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer’s disease and healthy controls

Author

Tiepolt, Solveig, primary, Becker, Georg-Alexander, additional, Wilke, Stephan, additional, Cecchin, Diego, additional, Rullmann, Michael, additional, Meyer, Philipp M., additional, Barthel, Henryk, additional, Hesse, Swen, additional, Patt, Marianne, additional, Luthardt, Julia, additional, Wagenknecht, Gudrun, additional, Sattler, Bernhard, additional, Deuther-Conrad, Winnie, additional, Ludwig, Friedrich-Alexander, additional, Fischer, Steffen, additional, Gertz, Hermann-Josef, additional, Smits, René, additional, Hoepping, Alexander, additional, Steinbach, Jörg, additional, Brust, Peter, additional, and Sabri, Osama, additional

Published
2020
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134. Development of Novel Analogs of the Monocarboxylate Transporter Ligand FACH and Biological Validation of One Potential Radiotracer for Positron Emission Tomography (PET) Imaging

Author

Sadeghzadeh, Masoud, primary, Wenzel, Barbara, additional, Gündel, Daniel, additional, Deuther-Conrad, Winnie, additional, Toussaint, Magali, additional, Moldovan, Rareş-Petru, additional, Fischer, Steffen, additional, Ludwig, Friedrich-Alexander, additional, Teodoro, Rodrigo, additional, Jonnalagadda, Shirisha, additional, Jonnalagadda, Sravan K., additional, Schüürmann, Gerrit, additional, Mereddy, Venkatram R., additional, Drewes, Lester R., additional, and Brust, Peter, additional

Published
2020
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135. Development of a Radiofluorinated Adenosine A2B Receptor Antagonist as Potential Ligand for PET Imaging

Author

Lindemann, Marcel, primary, Moldovan, Rareş-Petru, additional, Hinz, Sonja, additional, Deuther-Conrad, Winnie, additional, Gündel, Daniel, additional, Dukic-Stefanovic, Sladjana, additional, Toussaint, Magali, additional, Teodoro, Rodrigo, additional, Juhl, Cathleen, additional, Steinbach, Jörg, additional, Brust, Peter, additional, Müller, Christa E., additional, and Wenzel, Barbara, additional

Published
2020
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136. Preclinical Incorporation Dosimetry of [18F]FACH—A Novel 18F-Labeled MCT1/MCT4 Lactate Transporter Inhibitor for Imaging Cancer Metabolism with PET

Author

Sattler, Bernhard, primary, Kranz, Mathias, additional, Wenzel, Barbara, additional, Jain, Nalin T., additional, Moldovan, Rareş-Petru, additional, Toussaint, Magali, additional, Deuther-Conrad, Winnie, additional, Ludwig, Friedrich-Alexander, additional, Teodoro, Rodrigo, additional, Sattler, Tatjana, additional, Sadeghzadeh, Masoud, additional, Sabri, Osama, additional, and Brust, Peter, additional

Published
2020
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137. PET Imaging of the Adenosine A2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [18F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy

Author

Schröder, Susann, primary, Lai, Thu Hang, additional, Toussaint, Magali, additional, Kranz, Mathias, additional, Chovsepian, Alexandra, additional, Shang, Qi, additional, Dukić-Stefanović, Sladjana, additional, Deuther-Conrad, Winnie, additional, Teodoro, Rodrigo, additional, Wenzel, Barbara, additional, Moldovan, Rareş-Petru, additional, Pan-Montojo, Francisco, additional, and Brust, Peter, additional

Published
2020
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142. O-29 - Synthesis of novel PSMA ligands and preclinical evaluation of [99mTc]TcO-ABX474, a radioligand for SPECT imaging of prostate cancer

Author

Ludwig, Friedrich-Alexander, Lis, Christian, Ullrich, Martin, Lankau, Hans-Joachim, Sihver, Wiebke, Joseph, Desna, Eiselt, Erik, Meyer, Christoph, Guendel, Daniel, Deuther-Conrad, Winnie, Brust, Peter, Donat, Cornelius, Bachmann, Michael, Pietzsch, Hans-Jurgen, Pietzsch, Jens, Fischer, Steffen, Kopka, Klaus, and Hoepping, Alexander

Published
2022
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144. Synthesis and biological evaluation of new, potential MAO-B ligands

Author

Jevtić, Ivana, Lai, Hang, Penjišević, Jelena, Teodoro, Rodrigo, Dukic-Stefanovic, Sladjana, Brust, Peter, and Kostić-Rajačić, Slađana

Subjects
positron emission tomography, monoamine oxidase-B, 1-cinnamyl-4-arylpiperazine, radiofluorinated ligands
Abstract

The aim of this study was to develop highly specific radiofluorinated ligands for quantitative positron emission tomography (PET) imaging of monoamine oxidase-B (MAO-B) in brain. A series of 8 fluoro derivatives of 1-cinnamyl-4-arylpiperazine were synthesized by standard methods of organic synthesis. The affinity of the compounds was determined in a competitive binding assay using L-[3H] deprenyl as radioligand on rat brain homogenates. The KD of the radioligand was determined by homologous competition. An efficient, three-step procedure for the synthesis of the potential MAO-B ligands was developed. A competitive binding assay was established, using L-[3H]deprenyl as the radioligand, and rat brain membrane homogenate. The compounds were screened (three concentrations 10-9, 10-7 and 10-5) for their MAO-B affinity. We successfully synthesized a series of fluorinated MAO-B ligands. Unfortunately, their affinities toward MAO-B have proved to be rather low. To increase the affinity further modifications are needed.

Published
2019

145. [Dopamine Transporter SPECT with I-123 labelled FP-CIT (DaTSCANTM)]

Author

Tatsch, Klaus, Buchert, Ralph, Bartenstein, Peter, Barthel, Henryk, Boecker, Henning, Brust, Peter, Drzezga, Alexander, La Fougère, Christian, Gründer, Gerhard, Grünwald, Frank, Krause, Bernd-J., Kuwert, Torsten, Langen, Karl-Josef, Rominger, Axel Oliver, Sabri, Osama, Schreckenberger, Mathias, and Meyer, Philipp T.

Subjects
610 Medicine & health
Abstract

The aim of the S1 guideline is to assist in establishing the indication and in performing, interpreting and reporting SPECT investigations of the dopamine transporter (DAT) with DaTSCANTM. Compared to the preceding version dated from 2007 the current update considers relevant new publications, the guidelines of the European (EANM) and Society of Nuclear Medicine (SNM), and the current version of the S3 guideline of the German Society of Neurology on "Idiopathic Parkinsonsian Syndrome". In addition new technical developments are incorporated.

Published
2019
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148. Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Author

Ritawidya, Rien, Ludwig, Friedrich-Alexander, Briel, Detlef, Brust, Peter, Scheunemann, Matthias, Ritawidya, Rien, Ludwig, Friedrich-Alexander, Briel, Detlef, Brust, Peter, and Scheunemann, Matthias

Abstract

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

Published
2019

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